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| United States Patent |
5,187,100
|
|
Matzinger
, et al.
|
February 16, 1993
|
Dispersion to limit penetration of aqueous solutions into a membrane
Abstract
A control solution for use with a porous reagent strip comprises a flexible
semisolid polymer dispersed in water, such as polyvinyl acetate in
distilled water, with appropriate control glucose concentration levels.
This solution is useful in mimicking whole blood in conjunction with
porous reagent strips to determine compliance of the strips and meters to
established measurement and performance criteria.
| Inventors:
|
Matzinger; David P. (Menlo Park, CA);
Teodorczyk; Maria (Palo Alto, CA);
Poulos; Darwin R. (Los Altos, CA)
|
| Assignee:
|
Lifescan, Inc. (Mountain View, CA)
|
| Appl. No.:
|
795285 |
| Filed:
|
November 19, 1991 |
| Current U.S. Class: |
436/16; 252/408.1; 422/56; 422/61; 435/14; 436/14; 516/77; 516/DIG.2; 524/563 |
| Intern'l Class: |
G01N 031/00 |
| Field of Search: |
436/8-18,528,533,534
422/56,61
435/14
252/408.1,352
524/563
|
References Cited
U.S. Patent Documents
| 3558522 | Jan., 1971 | Louderback et al. | 436/10.
|
| 4020006 | Apr., 1977 | Parker | 436/8.
|
| 4133774 | Jan., 1979 | Brynko et al. | 252/62.
|
| 4151108 | Apr., 1979 | Sorensen et al. | 436/11.
|
| 4220698 | Sep., 1980 | Brynko et al. | 430/109.
|
| 4576604 | Mar., 1986 | Guittard et al. | 424/473.
|
| 4729959 | Mar., 1988 | Ryan | 436/14.
|
Primary Examiner: Johnston; Jill A.
Assistant Examiner: Bhat; N.
Parent Case Text
This is a continuation of application Ser. No. 07/530,044, filed May 29,
1990, now abandoned.
Claims
What is claimed is:
1. A control solution which mimics whole blood, for use with a porous
reagent strip comprising: a suspension of about 40% to about 55% solid
polyvinyl acetate particles dispersed in water, and a dispersant to
maintain said particles in suspension and glucose.
2. The solution of claim 1 wherein the dispersant is silicon dioxide.
3. The solution of claim 1 wherein the ratio of polyvinyl acetate
suspension to water by weight is between 1:5 and 1:8.
4. The solution of claim 3 further comprising an offset adjusting dye for
use with a reflectance measurement system.
5. The solution of claim 4 further comprising 0.0075% copper phthalocyanine
tetrasulfonic acid tetrasodium salt.
6. The solution of claim 3 further comprising polyvinyl acetate having a
particle size between 0.5 and 10 microns.
7. A control solution for use with a porous reagent strip having about 0.8
micron diameter pore size, said solution mimicking whole blood on said
strip, comprising: a 40%-55% polyvinyl acetate suspension and water in a
ratio of between 1:5 and 1:8 by weight, a dispersant to maintain said
polyvinyl acetate in suspension and glucose.
8. The solution of claim 7 wherein the ratio of polyvinyl acetate
suspension to water is about 1:6.
9. The solution of claim 8 further comprising 0.0075% copper phthalocyanine
tetrasulfonic acid tetrasodium salt.
10. The solution of claim 8 wherein the dispersant is silicon dioxide.
11. The solution of claim 8 wherein the amount of solid polyvinyl acetate
in the polymer suspension is between about 40% to about 55%.
Description
FIELD OF THE INVENTION
This invention relates to a dispersion for use in a membrane. More
specifically, the invention relates to a dispersion used to inhibit
penetration of aqueous solutions in a membrane. Most specifically, the
invention relates to a dispersion to inhibit penetration of aqueous
solutions in a membrane, where the dispersion is used in a control
solution useful in the quality control and performance verification of
glucose measuring meters and reagent strips.
BACKGROUND OF THE INVENTION
Reagent strips are quite popular for use in colorimetric reactions, in
which strip color is read by a hand-held meter, specifically, reagent
strips are useful in the determination of analyte levels in blood. Even
more specifically, reagent strips have been useful in the determination of
glucose levels in whole blood. Blood samples are placed on the reagent
strip, and after reaction with components embedded in the strips, a
determination of glucose levels in whole blood is made. The meter is
capable of discerning information from the reaction to determine glucose
levels in whole blood. Measuring meters, such as glucose measuring meters,
and reagent strips, such as glucose measuring reagent strips, vary in
accuracy and preciseness of measuring capabilities. It is therefore
necessary to provide a monitoring agent, known as a control solution,
which determines whether meters and strips are rendering meaningful
descriptions of glucose levels. Of course, it is important to have this
solution act in as close as possible a manner to the sample, i.e., whole
blood.
In porous membrane-based reagent strips, red blood cells (erythrocytes)
play an important part in controlling sample flow. When whole blood is
applied to the top surface of the membrane, the liquid portion of the
blood (plasma) immediately penetrates the porous structure, drawn in by
capillary action. As plasma is drawn toward the surface of the membrane,
it carries erythrocytes with it. When the erythrocytes contact the surface
of the membrane, they are prevented from entering the membrane by pores
which are smaller than the erythrocytes. The erythrocytes may rupture due
to surface properties of the membrane or capillary suction, releasing
their liquid contents into the membrane, but the erythrocyte cell membrane
(ruptured or not) remains at the reagent membrane surface, blocking
progress of plasma into the pores. When all of the surface pores are
covered by erythrocytes, all flow of plasma into the reagent membrane
ceases.
This flow control feature of whole blood is important for three reasons.
First, if flow of plasma were to continue unimpeded, gravity would cause
excess fluid to accumulate on the lower surface of the membrane where
reading takes place. This excess fluid would impede accurate reflectance
measurements of developed color on the reading surface. Second, continued
delivery of analyte (i.e., glucose in the case of a glucose reagent strip)
to the reagent system results in increasing color intensity as long as
flow continues. In contrast, if plasma flow is stopped upon reaching the
reading surface of the membrane, then the analyte sample size is
controlled, and color variation ceases when this analyte is completely
reacted. Third, in the absence of a flow controlling factor, plasma will
be drawn into the membrane surrounding the sample application zone,
carrying with it reagents and developed dyes, and depleting the
concentration of these chemicals in the center of the zone.
Separately or in combination, the above three effects inhibit the ability
of the system to reproducibly measure analyte levels in aqueous solutions.
Thus, when analyte is presented in an artificial matrix (control
solution), better precision is obtained if this artificial matrix
possesses flow control characteristics similar to whole blood. Precision
is important with control solution because typically the reagent
strip/meter system is said to be functioning properly if the control
solution produces a reading in a prescribed range. As the imprecision of
the system increases, this range must be broadened, and the value of a
single control test as an indication of system performance decreases.
Previous control solutions have attempted to mimic whole blood samples on
reagent strips, but for reasons listed below, control solution
reproducibility is difficult to attain. Current control solutions are made
viscous by the addition of water-soluble polymers such as methyl
cellulose, polyvinylpyrrolidone or hydroxypropyl cellulose. This increased
viscosity greatly slows down, but does not completely eliminate the
formation of excess solution on the reading surface. Thus, a
viscosity-modified control solution give>better precision than an
unmodified aqueous control, but does not operate as well as blood. In
addition, the high viscosity necessary to significantly slow the flow
makes the control solution difficult to handle during manufacture and
dispensing.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a control solution
which mimics whole blood.
It is further an object of the invention to provide a control solution
which mimics the performance of whole blood on porous reagent strips by
mimicking flow properties of whole blood.
It is yet another object of the invention to provide a control solution
which mimics the performance of whole blood when used on porous reagent
strips for testing glucose concentration levels in whole blood.
It is yet another object of the invention to provide a control solution
including known levels of glucose useful with a porous reagent strip in
combination with a glucose measurement meter.
It is a final object of the invention to provide a control solution which
is useful over a wide range of blood glucose concentrations to mimic blood
when placed on a reagent strip useful with meters for testing blood
glucose levels, in order to verify compliance to performance
characteristics of both reagent strip and meter.
These and other objects of the invention are achieved in a two-phase
dispersion of deformable particles in an aqueous medium. The dispersion
comprises particles of a non-water soluble polymer dispersed in water,
coupled with controlled levels of glucose. The deformable solid particles
are dispersed in water so that the bulk solution is essentially inviscid.
The particles suspended in the bulk solution are prevented from coalescing
in the water in which they are suspended.
It has been found that one useful combination of a polymer suspended
aqueous medium where the dispersion mimics the performance of blood in
reagent strips used in glucose measurements is a suspension of polyvinyl
acetate particles in water. The polymer is insoluble in water, and a
surfactant suspends the particles in the water to form a dispersion. Best
performance is obtained in a ratio of one part 40-55% solid dispersion in
six parts water. When various glucose concentration levels are added to
the emulsion, the emulsion is useful in mimicking blood when placed on
reagent strips for determination of glucose levels. This embodiment
becomes useful as a control solution to determine compliance of porous
reagent strips and meters which measure glucose.
These and other objects of the invention will be better understood by the
following detailed description of the drawings in connection with the
detail description of the invention .
DETAIL DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a reagent strip useful in the measuring of
glucose levels in blood; and
FIG. 2 is a cross sectional view of a reagent strip useful in the
measurement of glucose levels in blood.
DETAILED DESCRIPTION OF THE INVENTION
As seen in FIGS. 1 and 2, a reagent strip 10 useful in the measuring of
whole blood typically will have a porous open-celled matrix 11 capable of
transporting a liquid. On one side 12, a blood sample will be placed at
hole 14. Blood will seep from capillary effect to the opposite side 13 of
the matrix 11. Glucose in the blood reacts with reagents embedded within
the matrix 11. When passing into the matrix 11, red blood cells disperse
and close the pores of the matrix, so that a limited volume of liquid
phase flows into the reaction zone and an accurate reflectance measurement
can be made on opposite side 13.
Generally, glucose in the liquid portion of the sample then reacts to
produce a colorimetric change, detectable by an optical meter into which
the reagent strip 10 is placed. This optical meter will then determine
levels of glucose or other analytes contained in the whole blood sample.
In order to determine whether the meters and reagent strips 10 are
operating properly, it is periodically useful to test them using a control
solution with a known concentration of glucose. It is this control
solution formulation which is the basis of the invention.
In formulation of an appropriate control solution, many factors go into
selection. Most specifically, it is desirable to obtain a control solution
which accurately mimics blood on porous reagent strips. It has been found
that an emulsion of semi-solid polymeric particles in an aqueous medium
most accurately mimics the performance of whole blood samples on a porous
glucose measuring reagent strip. In one typical measurement system, these
reagent strips have a 0.8 micron pore size through which the whole blood
sample seeps. It is noticed that in whole blood samples, the liquid will
seep through the pores in a reagent strip of this size, and erythrocytes
remain on the sample side 12 of the reagent strip 10 effectively limiting
sample flow by closing the pores of the matrix 11. It is therefore
desirable to create a control solution which closes pores in the reagent
strip, similar to the way erythrocytes behave in whole blood.
Furthermore, it has been discovered that various polymers effectively
behave like erythrocytes in whole blood, especially those "tacky" polymers
containing flexible particles, as later explained.
Polyvinyl acetate having about 0.5 to 10.0 microns particle size when
suspended in water almost accurately mimics these characteristics of whole
blood samples. These particles of polyvinyl acetate alone form a very
viscous fluid; they must be dispersed in water so that the bulk liquid
solution formed from the emulsion is essentially inviscid, like blood.
Ideally, these flexible, semi-solid particles remain dispersed in control
solution throughout its use in mimicking a blood sample.
In control levels of 300 mg/dl glucose concentration, a polyvinyl acetate
suspension commercially available as a liquid with approximately 40% to
55% solid by weight performs admirably when placed in a weight ratio of
suspension to water between 1:2 and 1:10. Most specifically, ratios of
about 1:5 up to about 1:6 per weight with water perform best, especially a
ratio of about 1:6. This ratio provides reproducibility for glucose
readings and penetration of solutions through a typical porous glucose
reading membrane. With other membranes, polyvinyl acetate to water ratios
would differ, and it is the intention of this invention to disclose the
use of the polyvinyl acetate dispersion as a control solution for a
variety of porous strips over a variety of measurement situations.
In certain glucose measuring systems, such as the One-Touch.TM. system
manufactured by the assignee of this invention, whole blood readings are
taken at 635 nm and 700 nm wavelengths. It is necessary in such a system
to provide an offset adjuster which permits the system to read proper
glucose levels at these wavelengths. Through experimentation, copper
phthalocyanine tetrasulfonic acid tetrasodium salt performed admirably in
control solution both at 0 mg/dl and 300 mg/dl glucose.
The polyvinyl acetate control solution forms a dispersion, a two-phase
system in which one phase, the polyvinyl acetate particles, are
distributed about the water phase. Because the particles interact with the
medium, the proper level of dispersion may not necessarily be maintained.
Consequently, due to the attractive force between polyvinyl acetate
particles, there is a tendency for the dispersed particles to come
together to form large units, unless there is a mechanism preventing such
attraction of polyvinyl acetate particles.
If the polymer particles settle to the bottom of the control solution vial,
the performance of the control solution lessens. In addition, resuspending
particles is an additional step for the user. Thus a dispersion stabilizer
is necessary to cause the system to resist forming these flocculates. It
has been found that AEROSIL.TM. 200 comprising very fine spherical silicon
dioxide particles (between 7 nm and 40 nm diameter) acts well as a
dispersion stabilizer in the polyvinyl acetate emulsion, and also provides
for rapid redispersion of polymer particles. Other surfactants may be
useful as dispersion stabilizers, such as those surfactants which are
residues of the emulsion polymerization process which forms polyvinyl
acetate particles.
Initially, the bulk polyvinyl acetate emulsion has an approximate pH
between 4.5 and 6.0. Ready to use control solution of the present
invention has a pH of about 4.9.+-.0.2. However, no change was noticed in
control performance within a pH between about 3.5 to about 5.9.
EXAMPLE I
In this example, four control solutions were formulated. Two were made
according to previous technology (viscosity modified with methyl
cellulose) and two according to the present invention, polyvinyl acetate.
Each pair was adjusted to glucose levels representing high and low control
levels:
______________________________________
Control Ingredient Amount
______________________________________
Methyl Cellulose
water 50 ml
Gantrez AN-139 450 ml
methyl cellulose
5 g
sodium benzoate 1 g
disodium EDTA 0.5 g
(stabilizer)
glucose 0.8 mg/ml - low
3.0 mg/ml - high
Polyvinyl Acetate
water 600 ml
43% solids polyvinyl
100 g
acetate
copper pthalocyanine
52.5 mg
3,4',4",4'"-tetrasulfonic
acid tetrasodium salt
Aerosil .TM. 200
700 mg
sodium benzoate 1400 mg
disodium EDTA 700 mg
(stabilizer)
Dow B (antifoamer)
140 mg
glucose 0.4 mg/ml - low
3.0 mg/ml - high
______________________________________
The methyl cellulose had a molecular weight such that a 2% solution in
water would have a viscosity of 4000 cp. Gantrez AN-139 comprises a 1.1%
solution which is pre-hydrolyze by heating until clear, then adjusted to
pH 6.7. The stabilizer and antifoamer are optional for performance of the
control solutions.
Each solution was tested with a number of different glucose reagent strip
lots (One Touch.TM. glucose reagent strips) in order to determine the
representative precision of each solution with this reagent strip.
Measurements were performed with a commercial glucose meter (One Touch.TM.
glucose monitor) according to the Manufacturer's Instructions:
______________________________________
# glucose
Control # lots replicates
(mg/dl) pooled Cv
______________________________________
Methyl 20 15 80 6.5%
Cellulose
Methyl 20 15 300 7.2
Cellulose
Polyvinyl
259 10 40 2.01
Acetate
Polyvinyl
259 5 300 3.22
Acetate
______________________________________
As the reproducibility of measuring a solution on a given reagent strip lot
gets better, the pooled Cv decreases. It can be seen from the above
results that the controls made according to this invention gave lower
pooled Cv's, and hence better precision, than the methyl cellulose
controls.
It was determined that our control solution performs well on actual porous
reagent membrane strips and glucose testing meters for glucose
concentrations between 0 mg/dl glucose and 600 mg/dl. The control solution
performs well on meters between 0 mg/dl glucose and 350 mg/dl glucose, or
well within the desirable human blood sample range.
EXAMPLE II
As a demonstration of the ability of various different commercially
available polymer suspensions to perform the flow control function
described above, test strips were constructed according to FIG. 1, except
that the matrix 11 was comprised of untreated 0.8 micron nylon membrane.
Mixtures of various polymer suspensions with water were prepared and
spotted onto the top of the strip, as with whole blood. After a 30 second
penetration time, the diameter of the wetted area on the side 13 was
measured to quantitate flow control due to the polymer particles. Since
the hole 14 was 4.8 mm in diameter, a wetted area of 4.8 mm would be
perfect flow control.
______________________________________
ratio of diam.
polymer of wetted
Polymer Polymer suspension:
area
Suspension type water (mm)
______________________________________
Union 76 vinyl/ 1:3 11
Unocal 3016 acrylic 1:1 9
2:1 7
1:0 5.5
Polidene chloride 1:4 8
33-080 1:0 5.5
Texigel acrylic 1:0 6
13-047
Borden vinyl 1:15 10
Glu-All 1:3 6
Scott Bader carboxy- 1:4 8
Texigel lated acrylic
1:0 6
13-302
Air Products
vinyl 7:1 9
Airflex acetate/ethy-
3:1 7
400 lene 1:1 5
______________________________________
Although some polymer suspensions are more efficient than others in terms
of controlling flow (i.e., achieve small wetted diameters with smaller
amounts of polymer), all are capable of some degree of flow control. Thus,
when a drop of this suspension is placed on the top side of the membrane,
the flexible particles modify the flow of the aqueous medium into the
membrane in a fashion similar to blood: the flexible particles deform to
the shape of the membrane surface or pores, effectively sealing the pores.
These particles may be comprised of any material flexible enough to deform
to the shape of the surface or pores, while viscous enough to resist flow
under the force of capillary action. Examples of such materials are
polymers which are "tacky" at room temperature, viscous solutions of
polymers, or viscous non-water soluble liquids such as oils.
The bulk viscosity of these controls is low, similar to blood, at the
concentration of particles necessary to produce the desired flow control
characteristics. Thus, these controls are easier to manufacture and
dispense than viscosity-modified controls.
Therefore, this invention is useful in control solution verification for
typical glucose testing monitors useful in combination with Porous reagent
strips. It is to be understood that the invention is to be derived from
the attached claims and their equivalents which follow.
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